INTRODUCTION
The echinocandins are a class of drugs that have made an enormous impact on the treatment of fun-gal infections. Less expensive than lipid formula-tions of amphotericin B, they have less toxicity than amphotericin products and fewer drug interactions than azoles. Efficacy for yeast/Candida species is comparable to amphotericin-based products, and they have activity against many mold species. Caspofungin was the first echinocandin approved by the FDA, coming on the market in 2001. Since then, two more products have been approved: mica-fungin (2005) and anidulamica-fungin (2006). The devel-opment of competition in the echinocandin market has prompted a class review of these drugs in order to determine the choice with the most favorable bal-ance of economics, safety and efficacy. The indica-tions, dosing and costs are summarized in Table 1. Mains pharmacological issues
The echinocandins are large, semisynthetic, injectable lipopeptides derived from fungal fer-mentation products (6, 15, 30). Their molecular weights range from 1,140 to 1,292 daltons. The echinocandins inhibit the growth of fungi by
interfering with the synthesis of the fungal cell wall component 1,3-ß-D-glucan, a large polysac-charide that provides rigidity to the cell wall. The pharmacokinetic properties of the echinocandins are quite similar, and are summarized in Table 2. Antifungal activity
All three of the currently available echinocandins have in vitro activity against a variety of species of Candida, Aspergillus and other opportunistic fungi. The relationship between in vitro activity and clinical efficacy against fungal isolates is unclear; interpretive criteria have not yet been defined (8). Tables 3 and 4 summarize the in vitro activity of the available echinocandins, according to consolidated literature evidences.
Caspofungin vs. Candida
The in vitro activity of caspofungin against Candida species has been well documented. In six studies using 7,109 clinical isolates of various species of Candida, caspofungin inhibited the overwhelming majority of isolates at concentra-tions ⱕ2 mcg/mL (19, 20, 27, 28, 36, 37). This held true even for fluconazole-resistant isolates.
Expansion of a recent class of broad-spectrum
antifungal agents: the echinocandins
Roberto Manfredi
Dipartimento di Medicina Interna, dell’Invecchiamento e delle Malattie Nefrologiche,
“Alma Mater Studiurum” Università degli Studi di Bologna, Policlinico S. Orsola-Malpighi, Bologna
Key Words: antifungal drugs, echinocandins, caspofungin, anidulafungin, micafungin, indications, clinical studies Espansione di una recente classe di agenti antimicotici ad ampio spettro: le echinocandine SUMMARY
The echinocandins show comparable efficacy in the treatment of candidemia and invasive candidiasis. Caspofungin and micafungin appear to be similarly efficacious in salvage therapy in aspergillosis; anidulafungin has excellent in vitro activity against Aspergillus species but as yet there are no sufficient clinical data for anidulafun-gin in this disease state. Each drug has minor advantages and disadvantages compared to the others of the same classe; however, there are large differences in the approved indications for the different drugs. The formulary selection process should consider the direct and indirect costs of the single agents; the characteristics of the patient population at risk for invasive mycosis, such as frequent use of interacting drugs and the burden of mon-itoring plasma drug levels of drugs; and the implications of using products for indications which have not been still approved (off-label indications).
Received January 26, 2009 Accepted March 5, 2009
R E V I E W
Corresponding author: Roberto Manfredi
c/o Malattie Infettive, Policlinico S. Orsola
Candida parapsilosis isolates tended to have higher MICs than other species, but most were inhibited at or below 2 mcg/mL, and one study reported a MIC90 >8 for 75 isolates of Candida guilliermondii (28). Two studies reported overall MICs for all isolates in aggregate; for 751 isolates the MICs were 0.25-0.5 mcg/mL (7, 8).
Micafungin vs. Candida
Three studies evaluated the in vitro activity of
micafungin against 551 clinical Candida isolates (22, 23, 35). In one study of 315 fluconazole-resistant isolates, the overall MIC90 was 0.06 mcg/mL; C. glabrata isolates were the most sen-sitive to micafungin, with an overall MIC90 of 0.015 mcg/mL for 110 isolates (22). A second study also found excellent activity against all species of Candida, although MICs for C. parap-silosis were among the highest, ranging from 0.5 to 2 mcg/mL (23).The third study found micafun-Table 1. Main characteristics of echinocandins
gin to be the least active when compared to sever-al azole antifungsever-als, amphotericin B and flucyto-sine, with an overall MIC90 for 164 isolates greater than 8 mcg/mL, but this finding was pri-marily due to the high MIC90s of the 16 isolates of C. parapsilosis (19).
Anidulafungin vs. Candida
The in vitro activity of anidulafungin against 3,251 clinical isolates of Candida species was evaluated in four studies (1, 5, 30, 37). Isolates of C. albicans and C. glabrata were highly suscepti-ble to anidulafungin in all the four studies, with MIC90s of less than 2 mcg/mL. Higher MICs val-ues were observed with isolates of C. parapsilosis in most of the studies, ranging from 2-8 mcg/mL. MICs for C. tropicalis, Candida dubliniensis, Candida famata and C. guilliermondii were also found to be higher in some studies (1, 30). Caspofungin vs. Other Fungi
The in vitro activity of caspofungin against 700 isolates of Aspergillus species was evaluated in three studies (6, 11, 12). The great majority of
iso-lates were highly susceptible to caspofungin, although in one study, the range of MICs for 13 isolates of Aspergillus fumigatus was 0.5->16 mcg/mL, with a mean MIC of 2.15 mcg/mL (11). The largest study included isolates from environ-mental sources as well as clinical sources; caspo-fungin was potently active with a MIC90 of less than 0.007 for all isolates regardless of the source (12). Espinel-Ingroff et al. also evaluated the in vitro activity of caspofungin against other oppor-tunistic fungi (11). Caspofungin proved moderately active against Cladophiliophora bantiana, Bipolaris species, Scedosporidium prolifififi cans, Blastomyces dermatitidis and Histoplasma capsula-tum, with MICs ranging from 2-8 mcg/mL. On the other hand, caspofungin tested inactive against Fusarium species, Rhizopus arrhizus, Cryptococcus neoformans and Trichosporon beigelii.
Micafungin vs. Other Fungi
The in vitro activity of micafungin against 596 environmental and clinical isolates of A. fumiga-tus was compared to that of five other antifungal agents (21). Micafungin exhibited a very low Table 3. In vitro activity of the different echinocandine molecules against Candida spp.
MIC90 (<0.007 mcg/mL) for all isolates regard-less of whether the organism was obtained from a clinical or environmental site. The in vitro activi-ty of micafungin against 16 species of molds was evaluated by Nakai et al. (25). Micafungin was highly active against all the six species of Aspergillus and had intermediate activity against Cladosporium trichoides, two Exophiala species and Fonsecaea pedrosoi. Micafungin was inactive against Absidia corymbifera, Cunninghamella elegans, two Rhizopus species, Fusarium solani and Pseudallescheria boydii.
Anidulafungin vs. Other Fungi
The in vitro antifungal activity of anidulafungin against Aspergillus spp. was initially compared to those of four other antifungal agents (6). Anidulafungin was highly active against all 68 strains, with MICs of 0.03 mcg/mL for all strains tested. Later, Zhanel et al. evaluated the in vitro activity of anidulafungin against 64 clinical iso-lates of Cryptococcus neoformans, Blastomyces dermatitidis and Aspergillus species (37). Anidulafungin potently inhibited all the five test-ed Aspergillus spp. It was ineffective against C. neoformans and B. dermatitidis.
Clinical trials
Caspofungin in Candida infections
Caspofungin was compared to amphotericin B deoxycholate for invasive candidiasis in a double-blind, randomized trial in adult patients (24). Eligible patients were adults with at least one pos-itive culture for Candida from blood or another sterile site plus at least one sign of infection. Stepdown therapy with oral fluconazole was per-mitted, if clinically warranted, after 10 days of IV therapy with the study drug. Patients were strati-fied according to APACHE score and randomized to receive either caspofungin as a 70-mg loading dose followed by 50 mg per day or amphotericin B at a dose of 0.6 to 0.7 mg/kg/day for non-tropenic patients and 0.7 to 1 mg/kg/day for neu-tropenic patients. The primary efficacy measure was overall response to therapy, with a favorable response defined as resolution of all symptoms and signs of the infection as well as microbiolog-ical eradication. Caspofungin would be consid-ered non-inferior to amphotericin B if there was less than 20% difference between the two study groups once APACHE scores and neutropenia were accounted for. The rates of favorable response at the end of IV therapy did not differ significantly between the two groups (73.4% for caspofungin vs. 61.75 for amphotericin B;
MITT analysis, no concomitant antifungal thera-py, no protocol violations that could interfere with efficacy assessment, appropriate evaluation at the end of therapy and receipt of study drugs for five days or more), the respective response rates were 80.7% and 64.9% (p=0.03); the criteria for non-inferiority were met. There were significantly more patients in the amphotericin group who had adverse events due to study drug (33 patients in the caspofungin MITT group; 28.9% vs. 73 patients in the amphotericin group; 58.4%; p=0.002). Signifi cantly more patients in the amphotericin group withdrew from the study due to adverse events (23.2% vs. 2.6%; p=0.003). The authors concluded that caspofungin was as effective as amphotericin B for the treatment of invasive candidiasis and was less toxic than amphotericin B.
Caspofungin was compared to amphotericin B deoxycholate for the treatment of endoscopically-confirmed esophageal candidiasis in a random-ized, double-blind trial (35). There were 128 patients enrolled in the study; they were random-ized to receive caspofungin 50 mg/day, caspofun-gin 70 mg/day, or amphotericin B deoxycholate 0.5 mg/kg/day. A favorable response was defined as the resolution of symptoms plus either clearing of esophageal lesions or an improvement of two or more grade levels. The response rates at the end of therapy were high for all three treatments (85% for caspofungin 50 mg, 96% for caspofungin 70 mg, and 72% for amphotericin B). While the response rates were higher for the caspofungin groups, the study was not designed to show supe-riority, so no conclusions about the relative effica-cy can be drawn. Response rates were similar regardless of the endoscopic grade of the lesions at enrollment.There was a significant diff erence in the proportion of patients who experienced adverse effects related to study drug (61% for caspofungin 50 mg, 68% for caspofungin 70 mg, and 93% for amphotericin; p<0.01 for each caspo-fungin group compared to amphotericin). The authors concluded that caspofungin was eff ective and well-tolerated in the treatment of esophageal candidiasis; the study was not designed to show non-inferiority.
clinical plus endoscopic response rates among the modified intent-to-treat population were 81% for the caspofungin group and 80% for the flucona-zole group. There were no significant differences between the groups in the rates of endoscopic response, clinical response or microbiological response. Relapse rates at the two-week and four-week follow-up visits did not differ significantly between the two treatment groups. Adverse events occurred in over 30% of the patients in each group, but only one event, a cellulitis in a flucona-zole-treated patient, was considered serious. There were no statistically significant differences between the groups in the incidence of individual adverse effects. The authors concluded that caspo-fungin was not inferior to fluconazole for the treatment of esophageal candidiasis, and that both drugs were well-tolerated.
Kartsonis et al. evaluated the safety and effi cacy of caspofungin in an open-label, compassionate-use study in adult patients with esophageal/pharyn-geal or invasive candidiasis who had failed therapy with an IV formulation of amphotericin B due to either inability to tolerate the drug or to refractory infection (14). The 37 patients enrolled received a 70-mg loading dose followed by 50 mg daily. The primary efficacy measure was a favorable response, defined for mucosal infections as resolu-tion or significant improvement in symptoms; a nor-mal follow-up oropharyngeal examination was also required in patients with oropharyngeal candidiasis. For invasive infections, a favorable response includ-ed resolution or significant improvement of signs and symptoms and radiographic studies and nega-tive results of follow-up cultures. Among patients with mucosal infections there was a favorable response rate of 86%; the rate among patients with invasive infections was 87%.
The favorable response rates were high (93% and 83%, respectively) among the 29 patients who had failed previous antifungal therapy. The response rates were similar regardless of the pathogen iden-tified. The mean duration of therapy was 31.4 days and was similar for patients with mucosal and sys-temic infections. Six patients died during the study, although none of the deaths was attributed to the use of caspofungin or to the Candida infection. One patient experienced an adverse event attrib-uted to caspofungin; a decreased platelet count was observed in a patient who was already thrombocy-topenic due to an underlying HIV disease.
The authors concluded that caspofungin is safe and effective in treating difficult Candida infections. Micafungin in Candida infections
DeWet et al. compared micafungin to fluconazole
in a randomized, double-blind, dose-ranging study in adult patients with endoscopically-con-firmed esophageal candidiasis (9). There were 251 patients randomized to receive either flucona-zole 200 mg IV daily or micafungin 50 mg, 100 mg or 150 mg IV daily. The primary endpoint of the study was endoscopically-confirmed cure, defined as a mucosal condition of zero (no evi-dence of lesions) on a 0-3 scale. The mean dura-tions of therapy in the micafungin 50 mg, 100 mg and 150 mg groups were 16.3, 13.4 and 14.0 days, respectively, while in the fluconazole group it was 14.0 days. The cure rates among micafungin-treat-ed patients were dose-relatmicafungin-treat-ed at 68.6%, 77.4% and 89.8% for the 50 mg, 100 mg and 150 mg doses and 86.7% for the fluconazole group in the ITT population. The two higher doses of micafungin had significantly higher cure rates than the 50 mg dose in the per-protocol population, and the 150 mg dose was significantly better than the 50 mg dose in the ITT population. Fluconazole also had a significantly higher cure rate than the 50 mg dose of micafungin, but the two higher doses of micafungin did not differ from fluconazole. For the analysis of secondary endpoint response rates, the authors combined the 100 mg and 150 mg doses of micafungin and compared the combined group to fluconazole, finding no significant differ-ence between the combined group and flucona-zole. Nine patients who received micafungin relapsed (one from the 50 mg group, five from the 100 mg group, and two from the 150 mg group); no patient from the fluconazole group experi-enced a relapse. Adverse events were common for patients receiving either drug, but these were gen-erally mild or moderate and did not differ signifi-cantly in nature between the groups. The authors concluded that micafungin at 100 mg or 150 mg per day was comparable to fluconazole in the treatment of esophageal candidiasis in patients with HIV infection.
condition, were 94.2% and 94.6%, respectively. Relapse rates did not differ significantly between the groups. Adverse event rates were similar and there was little difference between the groups in the type and frequency of events. The authors concluded that micafungin 150 mg daily was not inferior to fluconazole 200 mg daily for the treat-ment of esophageal candidiasis.
Ostrosky-Zeichner et al. evaluated the use of micafungin in 126 adult and pediatric patients with candidemia, including cases refractory to at least five days of therapy with an alternate sys-temic antifungal (27). Micafungin was dosed at 50 mg/day IV for C. albicans infections and 100 mg/day for Candida non-albicans or germ tube-negative infections in patients weighing 40 kg or more; the dose could be increased in 50 mg incre-ments as deemed necessary by the investigator. For patients weighing less than 40 kg, the dose was 1-2 mg/kg with the possibility of increasing the dose by 1 mg/kg increments. Micafungin was the sole therapy in patients with new infections; patients who had failed therapy could receive micafungin alone or in combination with their current therapy. The primary endpoint of the study was complete or partial response as determined by the investigators at the end of therapy. Among the 72 patients with new infections, 63 (87.5%) were treatment successes, with 55 (76.4%) complete responses; eight patients (11.1%) had partial responses. Seven patients (9.7%) had stable or progressive disease. Two patients were not evalu-able. Among the patients who had failed other therapy or prophylaxis, there were 54 (77.8%) who had a complete response, two (3.7%) who had a partial response and 10 (18.4%) who had stable or progressive disease. In this group of patients, the results were similar regardless of whether the patients were treated with micafungin alone or received micafungin in addition to their previous therapy. Overall response rates were greater than 80% for patients with infections due to C. albicans, C. glabrata, C. parapsilosis, and C. tropicalis. The response rate was lower (63.6%) with C. krusei infections. The highest response rates (?90%) were seen in patients receiving 75-150 mg/day. The overall response rate among adult the patients was 84.9%, while in children, including 11 neonates, it was 75.0%. Adverse effects were generally mild and occurred in only 7.4% of patients, a rate far lower than that observed in other clinical trials for micafungin. The most common adverse event, occurring in three (2%) patients, was thrombocytopenia. The
vage therapy in Candida bloodstream infections caused by a variety of species.
In a randomized, double-blind, non-inferiority study presented in abstract form at the 46th ICAAC, micafungin 100 mg/day and 150 mg/day were found to be non-inferior to caspofungin as a 70 mg loading dose followed by 50 mg/day in the treatment of invasive candidiasis (3). Patients received at least 10 days of study drug, after which they could be converted over to oral thera-py. The overall success rates in the intent-to-treat population were 73.9% for micafungin 100 mg/day, 70.3% for micafungin 150 mg/day and 71.4% for caspofungin. There was no advantage in dosing micafungin at 150 mg/day over 100 mg/day. There were no differences in safety among the three treatment arms.
Anidulafungin in Candida infections
Krause et al. evaluated the use of anidulafungin in the treatment of esophageal candidiasis in a randomized, dose-ranging study in 123 adult patients (17). Patients with positive blood or tis-sue cultures plus at least one sign or symptom of infection were randomized to receive 50 mg, 75 mg or 100 mg of IV anidulafungin once daily. The primary efficacy endpoint was global response, which included both clinical and microbiologic response. The global response rates were similar for all three doses (84%, 90% and 89% for the 50-mg, 75-mg and 100 mg-doses, respectively) at the end of therapy. The microbiological response rates were higher for the 75-mg and 100-mg doses (93% and 89%, respectively) than for the 50-mg dose (84%), but no statistical significance was reported for this difference. Just fewer than 30% of patients experienced an adverse event that was considered to be related to therapy. Most events were of mild or moderate severity. The most com-mon of these events was hypokalemia, occurring in four patients (10%) in the 50-mg
dose group. The authors concluded that anidula-fungin at 100 mg/day was as effective as other treatment options for esophageal candidiasis, and that it was well-tolerated.
place-among the intent-to-treat population were statisti-cally similar (86.7% for anidulafungin and 88.0% for fluconazole). The two treatments were similar in the rates of clinical and mycologic responses as well. Among the 462 patients who were evaluated endoscopically two weeks after the end of treat-ment, significantly more patients in the flucona-zole group had sustained endoscopic responses compared to the anidulafungin group (89.9% vs. 64.5%, respectively; p<0.001). Adverse events related to treatment occurred in 9.3% of patients in the anidulafungin group and 12.0% of patients in the fluconazole group. Few serious adverse events attributed to study drugs were reported. There were three patients in the fluconazole group and two in the anidulafungin group who withdrew due to adverse events. The authors concluded that the two drugs were similarly effective and well-toler-ated in treating esophageal candidiasis, but that fluconazole produced more sustained responses. There were more patients in the fluconazole group who were taking antiretrovirals drugs, a factor that could confound this analysis, but the authors do not indicate whether this difference was statistical-ly significant.
Caspofungin in Aspergillus infections
Maertens et al. evaluated caspofungin as salvage therapy for invasive aspergillosis (IA) in an open-label, noncomparative trial (20). Ninety patients with probable or proven IA who had disease pro-gression or lack of improvement with at least seven days of amphotericin B, lipid amphotericin B or itraconazole, or who had nephrotoxicity, increased serum transaminases or severe infusion reactions with those therapies were enrolled. The patients received a 70-mg loading dose IV and a 50-mg dose daily thereafter. The primary efficacy endpoint was clinical response. Among the modi-fied intent-to-treat population, 44.6% of patients had a favorable response to therapy, 7% had sta-ble disease, and 48% were considered treatment failures. Of those patients who had a favorable response, the great majority (89.2%) had a partial rather than a complete response. The response rates were significantly higher among patients with hematologic malignancies compared to those who had undergone HSCT (41.7% vs. 14.3%, respectively; p=0.01). Significantly higher response rates were seen among patients enrolled due to intolerance to conventional therapy com-pared to those with refractory infections (75.0% vs. 39.4%, respectively; p=0.03). Three of the 31 patients who had had a clinical response and were also evaluated at the four-week follow-up visit were found to have relapsed, despite receiving suppressive therapy with itraconazole. Most of the
study participants (93.3%) experienced at least one adverse effect, but only 12.2% of the partici-pants had an untoward effect that was considered to be related to caspofungin. All but one was con-sidered to be mild or moderate in severity. The authors concluded that caspofungin was effective and well-tolerated as salvage therapy in IA. A sec-ond study evaluated caspofungin as salvage ther-apy in 48 adult patients with IA using the same methods and enrollment criteria as the Maertens study (15). The majority of the enrollees (90%) had IA refractory to conventional therapy. The primary efficacy endpoint was clinical, radi-ographic and bronchoscopic response. The rate of favorable responses to caspofungin was 44.4%; of the favorable responses, 55% were partial responses and 45% were complete responses. The rate of unfavorable responses was 44.4% and for stable disease the rate was 11.1%. Factors associ-ated with a lower favorable response rate were underlying hematologic disease, extrapulmonary aspergillosis and infection refractory to multiple alternate agents, although the authors did not report p values for all these findings. Half of the patients enrolled in the study died during the study or follow-up period, with the majority of those (79%) dying as a result of IA. Five patients experienced adverse events associated with the use of caspofungin. Only one of these events (ana-phylaxis) was considered serious enough to dis-continue the study drug. The authors concluded that caspofungin was safe and effective as salvage therapy for IA.
Micafungin in Aspergillus infections
75% for chronic necrotizing pulmonary aspergillosis and 67% for pulmonary aspergillo-ma. The corresponding response rates for the 75 mg dose were 33%, “not available”, 67%, and 63%. Among the patients with candidiasis, all patients who received 50 mg and 75 mg doses responded; the two patients with esophageal can-didiasis who received 25 mg doses did not respond. The investigators did not differentiate between complete and partial responses. Adverse events related to micafungin were experienced by 30% of patients. The only event that was consid-ered serious was neutropenia in a patient who withdrew from the study. The authors concluded that micafungin was safe and effective in the treat-ment of deep-seated fungal infections.
Micafungin was evaluated in an open-label, non-comparative study in 331 patients with invasive aspergillosis who had failed or were intolerant to conventional therapy, or who had received less than 48 hours of other systemic antifungal thera-py (the so-called “primary” patients) (7). Patients with proven or possible invasive aspergillosis received micafungin 75 mg IV per day, or 1.5 mg/kg/day for patients weighing less than 40 kg. Th e dose could be increased in 75 mg/day or 1.5 mg/kg/day increments in 7-day intervals if cul-tures were persistently positive or if patients did not improve. Patients could continue to receive their prior therapy in addition to micafungin or could receive micafungin alone. The primary effi-cacy endpoint was favorable response to therapy based on clinical, radiologic and microbiologic evaluations. The rate of favorable (complete or partial) response among the modified intent-to-treat population was 35.6%, with another 11.1% of cases attaining stabilization of disease. The great majority of patients (85.3%) in this popula-tion were enrolled as refractory to their previous therapy. Among the refractory patients, 40.9% had a favorable response to micafungin as monothera-py (13.6% with a complete response and 27.3% with a partial response). The response rates for micafungin in combination were judged 34.5% favorable, 7.5% complete and 27.0% partial. Among the primary group, response rates were 50.0% favorable, 0% complete and
50% partial for patients receiving micafungin alone, and 29.4%, 17.6% and 11.8%, respectively for micafungin in combination. Lower response rates were seen in patients with neutropenia, HSCT and HIV/AIDS. The mean daily dose administered to adults was 111.4 ± 50.97 mg. Sixty-seven percent of patients required at least one dose escalation. Of the 145 patients seen for a
sidered to be attributable to study drug occurred in 31.9% of patients. The most commonly occurring effects were bilirubinemia, nausea, liver function test abnormalities and diarrhea. Moderate or severe adverse events occurred in 23.9% of patients and 3.1% of patients experienced a life-threatening adverse event. The authors concluded that micafungin is an effective treatment for inva-sive aspergillosis and is well-tolerated.
REFERENCES
1. Arévalo MP, Carillo-Mu?oz A-J, Salgado J, et al. Antifungal activity of the echinocandin anidulafungin (VER002, LY-303366) against yeast pathogens: a comparative study with M27-A microdilution method.
J Antimicrob Chemother 2003; 51:163-166
2. Barchiesi F, Schimizzi AM, Fothergill AW, et al. In
vitro activity of the new echinocandin, MK-0991,
against common and uncommon clinical isolates of
Candida species. Eur J Clin Microbiol Inf Dis 1999;
18:302-304
3. Betts RF, Rotstein C, Talwar D, et al. Comparison of micafungin and caspofungin for candidemia or inva-sive candidiasis. Presented as an abstract at the 46th Annual Interscience Conference on Antimicrobial Agents and Chemotherapy (ICAAC), September 27-30, 2006
4. Cuenca-Estrella M, Rodriguez D, Almirante B, et al.
In vitro susceptibilities of bloodstream isolates of Candida species to six antifungal agents: results from
a population-based active surveillance programme, Barcelona, Spain, 2002-2003. J Antimicrob
Chemother 2005; 55:194-199
5. Cuenca-Estrella M, Gomez-Lopez A, Mellado E, et al. Head-to-head comparison of the activities of current-ly available antifungal agents against 3,378 Spanish clinical isolates of yeasts and filamentous fungi.
Antimicrob Agents Chemother 2006; 50:917-921
6. Del Carmen Serrano M, Valverde-Conde A, Chávez M, et al. In vitro activity of voriconazole, itracona-zole, caspofungin, anidulafungin (VER-002, LY303366) and amphotericin B against Aspergillus spp. Diagn Microbiol Infect Dis 2003; 45:131-135 7. Denning DW, Marr KA, Lau WM, et al. Micafungin
(FK463), alone or in combination with other systemic antifungal agents, for the treatment of acute invasive aspergillosis. J Infect 2006; 53:337-349
8. De Rosa FG, Garazzino S, Pasero D, et al. Invasive candidiasis and candidemia: new guidelines. Minerva
Anestesiol 2008; Dec 17 (Epub ahead of print)
9. DeWet N, Llanos-Cuentas A, Suleiman J, et al. A ran-domized, double-blind, parallel-group, dose-finding study of micafungin compared with fluconazole for the treatment of esophageal candidiasis in HIV-positi-ve patients. Clin Infect Dis 2004; 39:842-849 10. DeWet NTE, Bester AJ, Viljoen JJ, et al. A
random-ized, double-blind, comparative trial of micafungin (FK463) vs. fl uconazole for the treatment of oesophageal candidiasis. Aliment Pharmacol Ther 2005; 21:899-90
oppor-tibility of 596 Aspergillus fumigatus strains isolated from outdoor air, hospital air, and clinical samples: Analysis by site of isolation. Antimicrob Agents
Chemother 2005; 49:3495-3497
13. Hebert MF, Smith HE, Marbury TC, et al. Pharmacokinetics of micafungin in healthy volun-teers, volunteers with moderate liver disease, and vol-unteers with renal dysfunction. J Clin Pharmacol 2005; 45:1145-1152
14. Kartsonis NA, Saah A, Lipka J, et al. Second-line therapy with caspofungin for mucosal or invasive can-didiasis: results from the caspofungin compassionate-use study. J Antimicrob Chemother 2004; 53:878-881 15. Kartsonis NA, Saah AJ, Lipka CJ, et al. Salvage
ther-apy with caspofungin for invasive aspergillosis. Results from the Caspofungin Compassionate Use Study. J Infect 2005; 50:196-205
16. Kohno S, Masaoka T, Yamaguchi H, et al. A multicen-ter, open-label clinical study of micafungin (FK463) in the treatment of deep-seated mycosis in Japan.
Scand J Infect Dis 2004; 36:372-379
17. Krause DS, Reinhardt J, Vasquez JA, et al. Phase 2, randomized, dose ranging study evaluating the safety and effi cacy of anidulafungin in invasive candidiasis and candidemia. Antimicrob Agents Chemother 2004; 48:2021-2024
18. Krause DS, Simjee AE, van Rensberg C, et al. A ran-domized, double-blind trial of anidulafungin versus fluconazole for the treatment of esophageal candidia-sis. Clin Infect Dis 2004; 39:770-775
19. Laverdiere M, Hoban D, Restieri C, et al. In vitro sus-ceptibilities of three new triazoles and one echinocan-din against Candida bloodstream isolates from cancer patients. J Antimicrob Chemother 2002; 50:119-123 20. Maertens J, Raad I, Petrikkos G, et al. Efficacy and
safety of caspofungin for treatment of invasive asper-gillosis in patients refractory to or intolerant of conventional antifungal therapy. Clin Infect Dis 2004; 39:1563-1571
21. Marco F, Pfaller MA, Messer SA, et al. Activity of MK-0991 (L-743,872), a new echinocandin, com-pared with those of LY303366 and four other antifun-gal agents tested against bloodstream isolates of
Candida species. Diagn Microbiol Infect Dis 1998;
31;33-37
22. Messer SA, Diekema DJ, Boyken L, et al. Activities of micafungin against 315 invasive clinical isolates of fl uconazole-resistant Candida spp. J Clin Microbiol 2006; 44:324-326
23. Mikamo H, Sato Y, Tamaya T. In vitro activity of FK463, a new water-soluble echinocandinlike lipopep-tide. J Antimicrob Chemother 2000; 46:485-487
24. Mora-Duarte J, Betts R, Rotstein C, et al. Comparison of caspofungin and amphotericin B for invasive can-didiasis. New Engl J Med 2002; 347:2020-2029 25. Nakai T, Uno J, Otomo K, et al. In vitro activity of
FK463, a novel lipopeptide antifungal agent, against a variety of clinically important molds. Chemother 2002; 48:78-81
26. Ostrosky-Zeichner L, Rex JH, Pappas PG, et al. Antifungal susceptibility survey of 2,000 bloodstream
Candida isolates in the United States. Antimicrob Agents Chemother 2003; 47:3149-3154
27. Ostrosky-Zeichner L, Kontoyiannis D, Raff alli J, et
al. International, open-label, noncomparative clinical
trial of micafungin alone and in combination for treat-ment of newly diagnosed and refractory candidemia.
Eur J Clin Microbiol Infect Dis 2005; 24:654-661
28. Pfaller MA, Diekema DJ, Messer SA, et al. In vitro activities of caspofungin compared with those of fl uconazole and itraconazole against 3,959 clinical iso-lates of Candida species, including 157 fluconazole-resistant isolates. Antimicrob Agents Chemother 2003; 47:1068-1071
29. Pfaller MA, Messer SA, Boyken L, et al. Caspofungin activity against clinical isolates of fluconazole-resist-ant Candida. J Clin Microbiol 2003; 41:5729-5731 30. Pfaller MA, Boyken L, Hollis RJ, et al. In vitro
activi-ties of anidulafungin against more than2,500 clinical isolates of Candida spp., including 315 isolates resistant to fluconazole. J Clin Microbiol 2005; 43:5425-5427 31. Product information. Cancidas (caspofungin).
Whitehouse Station, NJ: Merck & Co.; 2005
32. Product information. Eraxis (anidulafungin). New York, NY: Pfizer, Inc.; 2006
33. Product information. Mycamine (micafungin). Deerfield, IL: Astellas Pharma US, Inc.; 2005 34. Theuretzbacher U.
Pharmacokinetics/pharmacody-namics of echinocandins. Eur J Clin Microbiol Inf Dis 2004; 23:805-812
35. Villanueva A, Arathoon EG, Gotuzzo E, et al. A ran-domized, double-blind study of caspofungin versus amphotericin for the treatment of candidal esophagi-tis. Clin Infect Dis 2001; 33:1529-1535
36. Villanueva A, Gotuzzo E, Arathoon EG, et al. A dou-ble-blind, randomized study of caspofungin versus fl uconazole for the treatment of esophageal candidiasis.
Am J Med 2002; 113:294-299
37. Zhanel GG, Karlowsky JA, Harding GAJ, et al. In
vitro activity of a new semisynthetic echinocandin,
LY-303366, against systemic isolates of Candida species, Cryptococcus neoformans, Blastomyces
